Importance of Family History in
Gynecologic Cancer Prevention
Angela Thompson, MS, CGC Genetic Counselor
Froedtert & The Medical College of Wisconsin
Introduce role of genetic counselor
Discuss cancer genetics
Explain differences between sporadic, familial, and hereditary cancers
Explain importance of family history
Discuss HBOC and Lynch Syndrome
Discuss tools for your practice
Discuss special issues
Objectives
“This is your side of the family, you realize.”
Genetic Counselors
Genetic counselors are health professionals with specialized graduate degrees and experience in the areas of medical genetics and counseling
Cancer Genetic Counselors- Roles
Determine a patient’s risk for a hereditary cancer susceptibility syndrome based on personal/family history
Provide cancer risk assessment based on a patient’s family history
Determine what (if any) genetic tests are appropriate for a patient
Discuss risks, benefits, and limitations of genetic testing
Coordinate and interpret genetic tests
Provide psychosocial counseling
Chromosomes, DNA, and Genes
Cell Nucleus
Chromosomes
Gene
Protein
Adapted from Understanding Gene Testing, NIH, 1995
Disease-Associated Mutations
A mutation is a change in the normal base pair sequence
ALL CANCER IS GENETIC
BUT
NOT ALL CANCER IS HEREDITARY
Cancer results from the accumulation of mutations in cancer predisposing genes
Low, moderate-risk genes Shared lifestyles, environments
High-risk genes
Hereditary Ovarian Cancer
20-25% of women with a diagnosis of ovarian cancer carry a hereditary gene mutation Cancer J. 2012 Jul-Aug;18(4):320-7.
Hereditary Endometrial Cancer
5% of women with a diagnosis of uterine cancer carry a hereditary gene mutation
2-3% of women with endometrial cancer have Lynch syndrome
Histopathology 2013, 62, 2–30. Cancer J. 2012 Jul-Aug;18(4):338-42.
Importance of Identification
Why is it important to identify hereditary gynecologic cancer predisposition syndromes in families?
High risk of cancer development
Early-onset cancers
Multiple organ systems may be involved
Increased risk for second primary cancer
SPORADIC CANCER = FEW
OCCURRENCES OF CANCER IN FAMILY
Onset later in life
Few relatives with cancer
Uterine ca
at 70y
Unclear inheritance pattern: Chance alone Common environment/lifestyle factors Shared low, moderate-risk genes
Uterine ca
at 58y
Uterine
ca at
62y
FAMILIAL CANCER = CLUSTER OF CANCER
WITHIN FAMILIES
HEREDITARY CANCER
Multiple affected individuals in multiple generations
Early age of onset
Individuals with multiple primaries
Evidence of dominant inheritance
Specific cancer clusters
Family History Features Suggestive of a
Hereditary Cancer Syndrome
Multiple family members affected with cancer in multiple generations
Early onset cancer (before age 50)
Clustering of specific types of cancers
Breast and ovarian cancer in same family
Colon, uterine, and ovarian cancer in same family
Individuals with more than one cancer
Breast and ovarian cancers in one person
Rare cancers
Male breast cancer
Ethnic background
Hereditary Breast and
Ovarian Cancer Syndrome
(HBOC)
Hereditary Breast and Ovarian
Cancer Syndrome
BRCA1 Breast Cancer Gene 1
BRCA2 Breast Cancer Gene 2
1/400-1/800 individuals in the general population carry a BRCA1 or BRCA2 mutation
Cancer J. 2012 Jul-Aug;18(4):320-7.
BRCA1 and BRCA2 Mutations in the
Ashkenazi Jewish Population
An estimated 1 in 40 Ashkenazi Jews
carries a BRCA1 or BRCA2 mutation
185delAG
5382insC
6174delT
BRCA1
BRCA2
Cancer J. 2012 Jul-Aug;18(4):320-7.
46; TAH- BSO
d. 49;
Ovarian ca at 43
d. 48 ovarian ca @ 43
79 62; breast ca at 48
d. 65; Bladder ca; smoker
d. 60’s; MI d. 78
78 80 d. 70’s 70’s 70’s
d. 30’s; unknown cause
German Polish
-No Ashkenazi Jewish
ancestry
-No consanguinity
25
breast cancer:
~45%-80% (often
early onset) male breast
cancer
(3-12%)
ovarian cancer
(BRCA1: ~40%)
(BRCA2: ~20%)
BRCA1/2-Associated Cancers:
Lifetime Risks
Risk is increased for other cancers
including: pancreatic, prostate,
melanoma
Am J Hum Genet. 2003 Sep;73(3):709. Cancer J. 2012 Jul-Aug;18(4):320-7.
Ovarian Cancer Risk Management Options
Screening Concurrent transvaginal ultrasound and CA-
125 every 6 months starting at age 30y or 5-10y earlier than first diagnosis of ovarian cancer in family
Data suggests that screening is NOT effective for the early detection of ovarian tumors
J Med Genet 2009;46:593-597
Ovarian Cancer Risk Management Options
Risk Reduction- Surgery Bilateral salpingo-oophorectomy between ages
35y and 40y, or upon completion of childbearing, or individualized based on earliest onset of ovarian cancer in family
80-95% reduction in ovarian cancer risk in BRCA1/2 positive women following RRSO
NCCN Guidelines Version 1.2013 Hereditary Breast and/or Ovarian Cancer Syndrome
N Engl J Med. 2002;346(21):1616-1622. Cancer J. 2012 Jul-Aug;18(4):320-7.
Ovarian Cancer Risk Management Options
Risk Reduction- Chemoprevention
Consider oral contraceptive use
50% reduction in ovarian cancer risk for BRCA1/2 positive women using oral contraceptives
Risk appears to decrease with longer period of use
Conflicting data regarding OCP use and breast cancer risk for BRCA carriers
N Engl J Med 1998;339:424-428
Breast Cancer Risk Management Options
Screening
Monthly BSE beginning at age 18y
Semi annual clinical breast exam beginning at age 25y
Annual mammogram and breast MRI beginning at age 25, or individualized based on earliest breast cancer onset in family
Surgery
Discuss option of bilateral prophylactic mastectomy
Chemoprevention
Tamxoifen/Raloxifene
NCCN Guidelines Version 1.2013 Hereditary Breast and/or
Ovarian Cancer Syndrome
Genetic Evaluation Guidelines
Personal and/or family history: Premenopausal breast cancer (<50y)
Triple negative breast cancer <60y
Bilateral breast cancer
Ovarian cancer
Male breast cancer
Postmenopausal breast cancer with additional relatives with breast cancer (especially if young age of onset)
Known hereditary cancer susceptibility syndrome
Adapted from: NCCN Guidelines Version 1.2013 Hereditary Breast and/or Ovarian Cancer Syndrome
Lynch Syndrome
(HNPCC)
Lynch syndrome
MLH1
MSH2
MSH6
PMS2
EPCAM (TACSTD1)
Features of Lynch Syndrome
Early but variable age at CRC
diagnosis (~45 years)
Typically right-sided tumors
Extracolonic cancers: endometrium,
ovary, stomach, urinary tract, small
bowel, bile ducts, sebaceous skin
tumors
42 45
Colon ca @
44
46 44
Colon ca
@ 41
38 44 40
Uterine
ca @
37
39
Uterine
ca @
39
68
Colon ca @
42, Uterine
ca @ 56
72 d. 65
Lung ca
@ 64
(smoker)
d. 72
Colon ca @ 70
d. 48
Glioblastoma
Multiforme @
46
72 68 d. 48
Stroke
d. 72
MI
d. 70
MI
d. 74
Lung ca
@ 73
(smoker)
69 64
NCCN Colorectal Cancer Screening Version 2.2012
Uterine/Ovarian Cancer Risk
Management Options
Screening
Annual office endometrial sampling is an option
Transvaginal ultrasound, CA-125
There is no clear evidence to support screening for endometrial cancer in Lynch syndrome
No evidence to support routine ovarian cancer screening
NCCN Colorectal Cancer Screening Version 2.2012
Uterine/Ovarian Cancer Risk
Management Options
Risk Reduction- Surgery
Prophylactic TAH-BSO should be considered after childbearing is complete
Risk Reduction- Chemoprevention
Oral contraceptives reduce risk for endometrial and ovarian cancer in the general population, although efficacy in women with Lynch syndrome has not yet been determined
J. 2012 Jul-Aug;18(4):338-42
Management- Men and Women
Colon cancer Colonoscopy at age 20-25y or 2-5y prior to earliest CRC diagnosis in
family, repeat every 1-2y
Gastric and small bowel cancer Consider EGD, with extended duodenoscopy and polypectomy at 2-3y
intervals beginning at age 30-35
Consider capsule endoscopy for small bowel cancer at 2-3y intervals beginning at age 30-35
Urothelial cancer Consider annual urinalysis beginning at age 25-30y
Pancreatic cancer Limited data, no current guideline
High-risk programs: consider annual endoscopic ultrasound and MRI
NCCN Colorectal Cancer Screening Version 2.2012
Case Examples
45
Colon ca @
44
46 44
Colon ca
@ 41
38 44 40
Uterine
ca @
37
39
Uterine
ca @
39
68
Colon ca @
42, Uterine
ca @ 56
72 d. 65
Lung ca
@ 64
(smoker)
d. 72
Colon ca @ 70
d. 48
Glioblastoma
Multiforme @
46
72 68 d. 48
Stroke
d. 72
MI
d. 70
MI
d. 74
Lung ca
@ 73
(smoker)
69 64
Case 1
MSH2 +
MSH2 -
42
Case 1
Patient with Lynch syndrome
Increased risk for endometrial and ovarian cancer
Should consider prophylactic TAH-BSO
Patient’s sister who tested negative for the familial MSH2 mutation
Average risk for Lynch-associated cancers
38 44
68
72 d. 65
d. 72
Colon ca @ 70
d. 86
72 68 d. 48
Stroke
d. 72
MI
d. 70
MI
d. 74
Lung ca
@ 73
(smoker)
69 64
25
45
Case 2
Colon ca @ 65
Case 2
Suspicion for LS is low
No genetic testing for family indicated at this time
Risk for gynecologic malignancies likely not increased over the general population risk
Genetic Evaluation Guidelines
Personal and/or family history of:
Colorectal cancer <50y
Endometrial cancer <50y
Colorectal and endometrial cancer in same individual
Ovarian cancer
Family History
Family History
A genetic answer for the ovarian and/or endometrial cancer in a family is not always available Undetectable mutation in known genes
(BRCA1, BRCA2, MLH1, MSH2, etc.)
Mutation(s) in unidentified gene(s)
Affected family members not able to undergo testing
Cancer may be due to shared lifestyle/environmental factors, shared personal risk factors
Family History
Ovarian Cancer
Having one first-degree relative with ovarian cancer increases a women’s risk to 1.5-4% risk
Having two affected relatives increases a women’s risk to 7%
Endometrial Cancer
Having one first-degree relative with endometrial cancer increases a women’s risk 2-fold
Cancer Treat Res. 2010; 156: 69-85
European Journal of Cancer Prevention 2009; 18:95-99.
Family History
Risk reducing surgery may be indicated for women with a strong family history
Definition for “strong family history” unclear
Recommendations for screening/prophylactic surgery provider-dependent
Family History- Tools For Your Practice
Who?
Siblings, children, parents, aunts, uncles, grandparents, cousins
Maternal AND paternal relatives
Ancestry
What?
Cancer type
Age of diagnosis
Unusual pathologic features
Multiple primaries
Family History- Tools For Your Practice
Extremely important to gather family history for each patient and to develop a process that works well for your clinic
Paper screening forms
Physician or nurse directed questioning
Family history questionnaires in the electronic medical record
On-line tools
Surgeon General Family History Tool
https://familyhistory.hhs.gov/fhh-web/home.action
Family History-Tools For Your Practice
***Family history changes over time***
Important to consider how a patient’s family history will be updated and stored in your clinic
Special Issues
Insurance
Genetic testing is expensive Varying coverage for genetic services
from one insurance company to another Most insurance companies cover genetic
testing when medically necessary
Some plans have direct exclusions to
genetic testing
Genetic counselors can help!
Genetic Discrimination- GINA
Genetic Information Nondiscrimination Act of 2008 (GINA)
Health insurance Prohibits use of genetic information in setting eligibility or
premium or contribution amounts by group and individual health insurers
Prohibits health insurers from requesting or requiring an individual to take a genetic test
Employment Prohibits use of genetic information by employers in making
decisions regarding hiring, firing, and promoting
Prohibits employers from requesting, requiring, or purchasing genetic information about an individual employee or family member
Questions?
References Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and
ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history; a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117-30.
Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:1811–4.
Weissman S, Weiss S, Newlin A. Genetic Testing by Cancer Site: Ovary. Cancer J. 2012 Jul-Aug;18(4):320-7.
Daniels M. Genetic Testing by Cancer Site: Uterus. Cancer J. 2012 Jul-Aug;18(4):338-42.
Folkins A, Longacre T A. Hereditary gynaecological malignancies: advances in screening and treatment. Histopathology 2013, 62, 2–30. DOI: 10.1111/his.12028
Evans DG, Gaarenstroom KN, Stirling D, et al. Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers. J Med Genet 2009;46:593-597.
Rebbeck TR, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations." N Engl J Med. 2002;346(21):1616-1622.
Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 1998;339:424-428.
References Shulman L, Dungan J. Cancer Genetics: Risks and Mechanisms of Cancer
in Women with Inherited Susceptibility to Epithelial Ovarian Cancer.
Cancer Treat Res. 2010; 156: 69-85.
Lucenteforte E, Talamini R et al. Family history of cancer and the risk of endometrial cancer. European Journal of Cancer Prevention 2009; 18:95-99.
NCCN Clinical Practice Guidelines in Oncology. Colorectal Cancer
Screening. Version 2.2012.
NCCN Clinical Practice Guidelines in Oncology. Genetics/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2013.
Scott M. Weissman, Randall Burt, James Church, Steve Erdman, Heather Hampel, Spring Holter, Kory Jasperson, Matt F. Kalady, Joy Larsen Haidle
and Henry T. Lynch, et al. J Genet Couns, 21(4): 484-93 (2012).